Browsing by Subject "Brain development"
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Item The effects of iron deficiency on the developing brain vasculature(2016-10) Nguyen, Thu AnIron deficiency is amongst the most severe and important micronutrient deficiencies, affecting millions of people globally, especially pregnant women and young children. Particularly, iron deficiency anemia (IDA) adversely affects the cognitive performance, behavior and growth of infants, preschool and school-aged children. Recently it was demonstrated that iron deficiency (FeD) during gestational and early postnatal life, induces angiogenesis/vasculogenesis in the developing neonatal rat brain. Previously, the impacts of FeD on the developing brain were reported in postnatal rats. Although FeD and thyroid hormone disruption share similar brain development deficits, combined FeD and impaired thyroidal status did not alter the developing brain vasculature in neonatal rats. Hence, the altered vasculature is an important independent effect of FeD on the developing brain. In this study, I further demonstrated that the angiogenesis effect of FeD is evident since birth and continues into the postnatal stage. Moreover, previous research showed restoration of other aspects of FeD’s impacts on the neonatal rat brain with Fe repletion or supplementation. Therefore, I hypothesized that the angiogenesis effects in developing Fe deficient rat brains are reversible with Fe repletion. qPCR data showed an increase in brain mRNA level of endothelial cell marker genes and angiogenesis associated genes in the developing iron deficient rat brain compared to control at birth, postnatal days 7 and 14. FeD also increases vessel branch points suggesting the FeD induced angiogenesis occurs since birth in the neonatal rat brains. After iron repletion on postnatal day 7, mRNA level of the same genes and vessel branch points had no significant increase compared to control at postnatal day 14 and returned to approximately the same level as control at postnatal day 30. These results suggest that FeD induced angiogenesis could be reversible as evident by vessel regression upon iron repletion. Brain angiogenesis is critically regulated by hypoxia-inducible factor 1 (HIF1) which is activated during hypoxia. I hypothesized that neonatal FeD results in tissue hypoxia and activates hypoxia-inducible factor 1 alpha (HIF1α) leading to induction of expression of several genes associated with angiogenesis. Western blot densitometry indicated no significant difference in HIF1α expression in Fe deficient brains compared to control at postnatal day 7 and 14. Finally, since it is unknown whether the induced vasculature is beneficial or not to the Fe deficient developing brain, we also assessed mRNA level of an endothelial integrity marker, plasmalemmal vesicle- associated protein, PLVAP or PV-1 that was expressed in a fenestrated blood brain barrier. The mRNA level of PV-1 gene was not altered in both FeD and Fe repletion groups, however, PV-1 specific roles as a BBB integrity marker in the process of vessel sprouting remains to be determined. Overall, this study on the independent effects of FeD on the developing brain vasculature demonstrated reversibility of the induced blood vessels outgrowth with Fe repletion at postnatal day 7, however, it is unclear if hypoxic signaling through the HIF1 pathway via HIF1α activation contributes to brain angiogenesis due to FeD.